Familial and prodromal PD patients present a moderate burden of superficial frontal white matter hyperintensities, bilateral basal ganglia periventricular enlarged spaces, and one-third display lacunar thalamic strokes, while no known pathogenic coding variants in main PD causative genes were found in early-onset familial cSVD patients.
Key Findings
Results
Familial and prodromal PD patients showed significantly elevated superficial frontal white matter hyperintensities compared to age-matched controls.
The difference was statistically significant with a Bonferroni-corrected p-value of 3.46e-06
The cohort included 104 familial PD and PD prodromal patients and 48 age-matched controls from the PPMI publicly available database
White matter hyperintensities were assessed using the modified Scheltens scale on axial T2-FLAIR MRI sequences
The superficial frontal white matter hyperintensities were linked to a mild reduction of motor and cognitive function
Increased LRRK2 p.G2019S and p.R1441C variant penetrance was associated with this finding
Results
Familial and prodromal PD patients exhibited significantly elevated bilateral basal ganglia periventricular enlarged spaces compared to controls.
The difference was statistically significant with a Bonferroni-corrected p-value of 2.64e-03
Assessment was performed using the modified Scheltens scale on axial T2-FLAIR MRI sequences
The cohort consisted of 104 familial PD and PD prodromal patients and 48 age-matched controls
This finding represents a classic neuroradiological feature of cerebral small vessel disease (cSVD)
Results
Approximately one-third of familial PD patients displayed a burden of lacunar thalamic strokes associated with a moderate hypokinetic-rigid syndrome.
The p-value for lacunar thalamic strokes was 0.058, which did not reach Bonferroni-corrected significance
This finding was associated with a moderate hypokinetic-rigid syndrome
The observation suggests a potential overlap between familial PD and vascular parkinsonism (VP)
Results
No known pathogenic coding variants in the main PD causative genes were identified in a cohort of 96 early-onset familial cSVD Caucasian patients.
Whole exome sequencing was performed on 96 patients with familial cSVD and 243 elderly healthy individuals from the HEX database
Genes examined included VPS35, DJ1, PINK1, ATP13A2, PRKN, SNCA, LRRK2, GBA, MAPT, LAMP3, and STK39
The analysis focused on protein coding variability in the main PD-causing and risk genes
The patient cohort was specifically early-onset familial cSVD Caucasian patients
Methods
The study used a descriptive and exploratory analysis design to characterize cSVD neuroradiological features in familial PD.
The modified Scheltens scale was applied to axial T2-FLAIR MRI sequences
The PPMI (Parkinson's Progression Markers Initiative) publicly available database was the source for the PD cohort
The study investigated classic neuroradiological features of cSVD including white matter hyperintensities, periventricular enlarged spaces, and lacunar strokes
The study aimed to investigate whether PD and vascular parkinsonism may share a potential pathogenic link
Results
The familial PD cohort was enriched for LRRK2, GBA, and SNCA mutation carriers, and increased LRRK2 variant penetrance was associated with white matter hyperintensities.
Specific variants LRRK2 p.G2019S and p.R1441C showed increased penetrance associated with superficial frontal white matter hyperintensities
The cohort is described as a 'familial LRRK2, GBA and SNCA PD-PD prodromal cohort'
The study adds to understanding of potential cSVD hallmarks within this specific genetic cohort
What This Means
This research suggests that people with inherited (familial) forms of Parkinson's disease and those in the early stages before full symptoms develop (prodromal) show specific patterns of brain blood vessel damage that are normally associated with a different condition called cerebral small vessel disease. Using brain MRI scans from 104 familial Parkinson's patients and 48 healthy controls, the researchers found that Parkinson's patients had significantly more white matter changes in the frontal part of the brain and enlarged fluid spaces around structures called the basal ganglia. Additionally, about one-third of familial Parkinson's patients had small strokes in an area called the thalamus, which was linked to movement difficulties. These vascular brain changes were also associated with mild declines in both movement and thinking abilities.
In a separate analysis, the researchers performed genetic testing (whole exome sequencing) on 96 patients with a hereditary form of small vessel disease to look for known Parkinson's disease gene mutations. They found no known disease-causing variants in any of the 11 major Parkinson's-related genes examined, suggesting that common Parkinson's genetic mutations are not a major driver of familial small vessel disease in this group.
This research suggests there may be overlapping pathological mechanisms between familial Parkinson's disease and vascular brain disease, particularly in patients carrying LRRK2 gene variants. This could have implications for how clinicians interpret brain scans in Parkinson's patients and for understanding why some patients have more complex symptom profiles. The findings highlight the importance of evaluating vascular brain changes in familial Parkinson's disease, as these changes may contribute to the overall burden of symptoms.